Overcoming the imatinib-resistant BCR-ABL mutants with new ureidobenzothiazole chemotypes endowed with potent and...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Kinase inhibitors targeting BCR-ABL are crucial for chronic myeloid leukaemia (CML) treatment.
• Imatinib resistance, particularly the T315I mutation, limits the efficacy of current therapies.
• Developing novel inhibitors is essential to overcome drug resistance in CML.

Purpose of the Study:

• To design and identify novel benzothiazole derivatives as potent inhibitors of BCR-ABL, including imatinib-resistant mutants.
• To evaluate the inhibitory activity of these compounds against BCR-ABL^T315I.
• To assess the anticancer potential of the lead compound against various cancer cell lines.

Main Methods:

• Structure-based design of benzothiazole derivatives based on a previously identified lead compound (AKE-5l).
• Synthesis of a series of six compounds (2a-f), including the lead candidate AK-HW-90 (2b).
• In vitro evaluation of inhibitory activity against BCR-ABL^T315I using IC₅₀ values and assessment of anticancer potency against NCI-60 cancer cell lines.

Main Results:

• AK-HW-90 (2b) demonstrated potent inhibition of BCR-ABL^T315I with an IC₅₀ of 0.65 nM, significantly outperforming related compounds.
• Compound 2a also showed strong activity with an IC₅₀ of 2.0 nM against BCR-ABL^T315I.
• AK-HW-90 exhibited superior anticancer efficacy compared to imatinib in multiple cancer cell lines, including K-562 leukaemia cells.

Conclusions:

• AK-HW-90 is identified as a potent pan-BCR-ABL inhibitor effective against imatinib-resistant mutants, especially T315I.
• The compound demonstrates significant anticancer activity, suggesting its potential therapeutic value.
• AK-HW-90 represents a promising candidate for the treatment of chronic myeloid leukaemia and other cancers driven by BCR-ABL alterations.